This blog is now 9 years old. My first post was on February 26th 2003. Since then the early UK blog network that it was a part of has largely fallen away. Blogs then were used a bit more like Twitter, with multiple postings per day. These days, blogs have become less frenetic, have donned the corporate pajamas of old media, and twitter has become the initial chopping board for most issues. Sometimes for the good, sometimes, when perhaps more calm consideration is required, for the bad.

Some of the things I am interested in are now covered far better (and certainly more quickly) by others. The blog has at least outlived the credibility of Andrew Wakefield’s hoax theory about autism and MMR vaccine (if not the consequences of it), which was a pet hobby of mine (although my involvement in tackling anti-vaccinators goes back to internet newsgroups in the 1990s).

In any case, in the past year or two this blog had become moribund, despite a recent spurt of activity. As a procrastination outlet/tool, it allowed me space to think in a way that more formal and structured academic writing didn’t. Sometimes, the ability to write a quick blog post paradoxically seemed to get the juices flowing in order to tackle a bigger piece of work elsewhere (i.e. my PhD) and it improved my writing skills. Some of the material on this blog ended up in or inspired academic papers, posters, and letters to journals. However, it is time to move on.

Thanks to all those who have linked to, written comments on, and read the blog. Any future writings on the net will be hosted either at www.anthonycox.org, possible occasional pieces at Left Brain, Right Brain, or at another potential work-based project that is in the conceptual stage (or perhaps more accurately mild flirtation before dating stage).

The number of dead in the wake of the substandard medicines disaster in Pakistan continues to rise with approximately 140 patients killed. Another 50 are not expected to survive. The product involved was isosorbide mononitrate tablets, commonly used in heart failure and angina, which was provided free by the Punjab Institute for Cardiology to patients too poor to obtain their own drugs. Drug samples were analysed by the London School of Pharmacy, who discovered heavy contamination with pyrimethamine, an anti-malarial. There was no institution within Pakistan capable of performing the analysis, startling considering they manage to run a nuclear weapons programme.

Pyrimethamine is associated with blood dyscrasias such as leucopaenia, agranulocytosis, and thrombocytopenia even when used correctly due to its interference with folic acid metabolism. Acute overdosage also causes convulsions, tachycardia, respiratory depression, and circulatory collapse. In a cohort of ill cardiac patients it is unsurprising that deaths have occurred. Pyrimethamine’s half life of 4 days isn’t particularly helpful either, especially considering the patients would have been likely to be dosing themselves with 1 tablet twice a day.

On the regulatory front, there is some good news. The current lack of a regulator in Pakistan is no longer politically acceptable. There have been calls for a centralised regulatory authority, regional monitoring centres, as well as the development of clinical pharmacy services within hospitals. Sadly, the Pro-Vice Chancellor of the Dow University of Health Sciences couldn’t stop himself from saying “the element of conspiracy to damage the reputation and exports of Pakistani medicines could not be ruled out”, continuing the proud tradition of blaming foreign interests for Pakistan’s self-inflicted wounds.

Any regulator has a major job to do, and it is not clear that the Pakistan state is capable of creating such an institution. The Pakistan government is riddled with corruption, there are massive cost pressures, and the pharmaceutical industry appears to be run by non-expert profiteers willing to employ illiterate staff and child labour. How the pyrimethamine got into the tablets is as yet unknown, but it could even come down to the tablets being manufactured by people unable to read the labels on the containers of drugs.

In perhaps one of the most macabre turns in the whole debacle, the Pakistan Pharmaceuticals Manufacturers Association (PPMA) is compensating the families of the dead by offering each family two jobs within the pharmaceutical industry. They are to be given jobs to match their qualifications, so if they can read they may be considered over-qualified.

As if there wasn’t enough problems in the pharmaceutical industry in Pakistan, a factory exploded yesterday. Around 100 people are thought to be trapped in the building, with only a handful of women and children rescued. There is no effective health and safety for the workers, never mind the customers for their products.

I’ve recently finished Jon Ronson’s The Psychopath Test, which is an absolutely brilliant quirky journalistic journey through Broadmoor, Scientology and DSM IV. He had an interesting Guardian article on DIY science published on Friday. He interviewed the guy who attempted to split the atom in his house, but more interestingly (at least to me) was the section on Yvonne Pambakian’s attempts at drug development in her cottage:

Five years ago, on 20 June 2007, she made an emergency call from the cottage. Her 22-year-old sister, Yolanda Cox, had gone into anaphylactic shock. When the paramedics arrived, they asked Pambakian what had happened.

“I gave her a drug for her asthma,” she told them.

Yolanda was rushed to the Royal Free hospital where a doctor, Alexander Mackay, asked her and her mother to explain exactly what they’d injected into her.

“They wouldn’t say,” he later told the coroner. “They said I didn’t need to know anything and the drug was extremely safe.” It seemed they were trying to protect some secret ingredient they’d been developing. “Some time later,” Mackay told the coroner, “they brought in paper information in two files.” The family were, in fact, injecting each other in their kitchen with an experimental drug of their invention, which they’d called B71.

Yolanda died a week later, on 27 June 2007.

Pambakian and her mother, she tells the hearing, began their experiments back in the mid-90s, pooling their areas of expertise (she’s a GP, her mother an immunologist). One day, they had a kind of eureka moment. To summarise it: some diabetes sufferers have an autoantibody that’s responsible for their resistance to insulin, and the Pambakians supposed that, as insulin resistance is so uniquely destructive, if they could derive a peptide from the autoantibody, it would be uniquely curative. So they did, and they called it B71. They began posting patent applications. B71 would treat – and this is just a small sample – asthma, diabetes, psoriasis, eczema, Alzheimer’s, schizophrenia, depression, Parkinson’s, migraines, multiple sclerosis, premature baldness in men, obesity, inflammatory bowel disease, asthma, cystic fibrosis, insomnia, cancer and HIV.

This sort of thing is far more common than you’d think, particularly in the US where quack autism and cancer treatments are peddled in the name of “research”. Sometimes defended by the use of litigation.

NHS Trusts are now allowed to develop and purchase their own IT infrastructure, allowing for some competition from providers. Not all of these systems will be as successful as each other, but it is to be hoped that most are. At the very worst this mechanism will allow the best systems to survive and propagate, and spread the risk of failure. Having a state funded monopoly on IT using contractors always seemed a prescription for failure. What were the incentives to succeed?

Talking of prescriptions, the development of electronic prescribing systems within the NHS hospital sector does continue regardless. Currently a majority of NHS hospitals continue to use paper based prescribing systems, with all the risks of illegibility and slips and lapses such free reign provides to prescribers. NHS Trusts are contracting different suppliers for the provision of prescribing systems, in much the same way primary care was allowed to develop such systems (perhaps something that should have been learnt earlier).

In any case, what are the benefits of electronic prescribing? A new paper examining the introduction of two commercial electronic prescribing systems in two Australian teaching hospitals sheds some additional light on this.

Westbrook et al performed a before and after medication chart audit of 3,291 admissions at two hospitals. They examined 1,923 prescriptions prior to the introduction to electronic prescribing, and 1,368 following its introduction. This appears to have been a well conducted real-world study, with errors classified into procedural errors, system-related errors, and a severity assessment for the potential of the error to cause harm.

In total there were 11,168 prescribing errors in the 1,923 admissions prior to prescribing – no surprise to any clinical pharmacist. Both commercial e-prescribing systems reduced prescribing error rates by over 55% at both hospitals, despite some differences between the systems and cultures of the hospitals concerned. With regard to serious errors comparison of control wards in one of the hospitals showed a 44% serious error rate reduction with electronic prescribing. Large declines occurred in unclear, incomplete, and legal/procedural prescriptions. There was also some evidence of benefit of electronic decision support, with reductions in duplicate prescriptions.

Electronic prescribing also brings new system errors, which in this study manifested as new clinical errors. It was this propensity to produce new patterns of errors that led to a failure to demonstrate a reduction in overall clinical error rates (otherwise the reduction of clinical errors rates would have been significant). System errors varied with the system and hospital procedures. The authors contend that these errors could be designed or “tweaked” out of the systems, or by increasing training for prescribers. This study illustrates both the benefits of e-prescribing, and the necessity of local vigilance, and design, in the use of the system within the culture of the hospital it is employed within.

Luptak, 45, of Bismarck, N.D., was working on a house last week when he accidentally shot himself in the head with a nail gun, sending the nail 3 inches into his skull. As he lay on the floor, he thought about his wife and daughters, 7-year-old twins and a 15-year-old, bracing for the worst.
[...]
Dr. Tariq Janjua said the nail lodged in the middle of the brain’s two hemispheres, just grazing major artery vessels. Had the nail gone any direction either way, he added, Luptak’s story would have ended much differently.

“It’s a very rare combination of things,” Janjua said. “It can’t get better than this.”

On Saturday, Luptak showed off the 26 staples in his head and joked about craving bacon. He still struggles to flex his left leg, which is weak because the nail hit the part of the brain that directs leg motion, but he’s expected to fully recover and return home this week.

Modern day drug safety in developed countries does not generally involve poor product quality. This isn’t to say problems don’t arise, the FDA and MHRA had to shut Chiron’s vaccine plant in Liverpool for some time. Followers of the MHRA Drug Alerts service will also be aware of the drug recalls associated with manufacturing problems or errors. This is a marker of good regulation. FDA and EU regulators inspect the manufacturers of pharmaceuticals both within their countries and also those external suppliers with product licences. This is one of the reasons that one should be wary of buying pharmaceutical products over the internet – you may be buying counterfeit or poor quality medicine.

Elsewhere regulation can be shaky . In Panama in 2006 over 300 people were killed by diethylene glycol laced cough mixture. The diethylene glycol had arrived labelled as harmless glycerine from the relative regulatory desert of the Chinese pharmaceutical sector. In China, there have been numerous problems linked to pharmaceuticals and baby milk. In 2007, the head of the Chinese FDA, Zheng Xiaoyu, was executed. Executing people every so often is seen as the solution rather than improved regulation.

A similar problem seems to have arisen in Pakistan, with over a hundred people suspected to have been killed by suspected contaminated heart drugs given to 46,000 patients. This BBC report suggests bone marrow suppression is the problem, although the particular drug involved is not known. Samples have been sent out of the country for testing, since Pakistan doesn’t have the ability to test the drugs. One news report cites the Director of a government Drug Testing Laboratory (DTL) blaming poor prescribing for the deaths, but the story also highlights the severe problems facing regulators in a border-line failed state:

He believed that deaths caused by the suspected drugs in Punjab were actually caused by the prescription as doctors prescribed high doses of cholesterol-lowering drugs to heart patients and this was responsible for the fatal reactions. However, he acknowledged that the actual reason could only be determined once the drugs had been analysed and autopsies carried on the deceased.

On the other hand, there was no change in the electricity supply situation at the lab. Power was disconnected a couple of months ago due to the non-payment of dues to the Karachi Electric Supply Company (KESC) and officials were relying on a small generator to power their equipment.

Staff of the DTL admitted that since directions had been given to analyse these medicines on a priority basis, they were planning to acquire an illegal electricity connection (Kunda) to complete the task.

Three owners of pharmaceutical companies have been arrested. Another BBC video report ends with a man stating “They should hang them publicly in the squares, like they do in Saudi Arabia.” While the actual facts behind this case may take some time to find, the answer is not to find scapegoats to punish. Effective and open regulation is the answer, and for that you need effective and open government, not bodies hanging from lamp posts.

The news that the diagnosis of autism may be brought forward is primarily of importance because it may help identify children who will require specialised support. However, it is also interesting because it breaks the co-incidental temporal association that has been part of the reason the MMR vaccine-autism hypothesis gained traction. Since the behavioural cues for autism can’t be picked up well until after one year of age, parental concern about their child being different and autism diagnoses rose after administration of the MMR vaccine. This had unfortunate consequences for the perception of MMR vaccine’s safety.

Elsabbagh et al examined “brainwaves” (event-related potentials – ERPS) of babies with a familial risk of autism when presented with pictures of faces either gazing at the baby or away from the baby. Those children who went on to develop autism diagnoses had differing ERPs.

Although the evidence of fraud, failure to find epidemiological evidence to back-up Wakefield’s claims, and failure to find measles RNA that would have supported Wakefield’s work were enough to bury any scientific case for the MMR Vaccine-autism hypothesis, the fact that autism may now be diagnosed before the MMR vaccine lays a nice wreath on top.

Not all parents whose children developed autism blamed MMR vaccine, some parents were already aware of a “difference” about their child before MMR vaccine, but it is understandable how some parents would have made the connection with the vaccine. After all, it is a key part of how clinicians make connections between a drug and adverse event, and is a strong element of assessing causality (see Bradford-Hill criteria).

The causation in the MMR vaccine debacle was neatly illustrated in an article from Prescriber [Registration required] written by Paula McDonald (a former Consultant in Communicable Disease Control).

Aristotle’s concept of syllogisms, says if certain prepositions are met, something distinct will arise from necessity. However, he also noted false syllogisms (In the UK we have an entire publication devoted to generating them, called the Daily Mail). McDonald’s figure illustrates the usual example of the horse being classified as a cat, along with the example of teddy bears and MMR vaccine causing autism.

You could replace the teddy bears with Peppa the Pig, or some other Greenfieldian scare. However, it sounds more convincing with vaccines, afterall you are introducing foreign material into a healthy child (and vaccines do cause adverse events sometimes).

Convincing people a false syllogism is wrong is a lot harder, than pointing out that A could not have caused B, because B arose months before A happened. Temporal associations are how we make sense of the everyday world. We don’t blame tripping up on a kerb on the beer we were going to have in the pub later that night.

Barring a Skynet conspiracy to send Terminators with MMR vaccine back in time to cause autism, this looks like a useful point to make to parents concerned about the risk of autism with MMR vaccine. Quite what the anti-vaccination groups will do, like the UK JABS cult, is interesting. Perhaps they will move to attack other vaccines given earlier, such as meningitis C or diptheria? Alternatively, they may look to the misapplication of physics, perhaps taking comfort in the news that neutrinos may have travelled faster than light, as their comrades-in-arms the homeopaths did.

I have been failing in my attempts to document the harms of nail guns in human bodies. Hard as Nails No 9 was way back in 2008, and started in 2004. Here is the latest case. Man did not notice nail in brain.

Dante Autullo, 34, was in his workshop when a nail gun recoiled near his head.

But he had no idea the nail had entered his brain until the next day, when he began feeling nauseous.
[...]
Ms Glaenzer said she had no idea the nail had entered his skull when she cleaned a cut on his forehead.

Gail Glaenzer said he jokingly told her to get the TV cameras: “I’m one of those medical miracles”
She convinced him to go to the hospital after he felt nauseous for much of Wednesday.

Mr Autullo thought that the nail gun had simply hit his forehead, but realised later that when the gun came in contact with his head, the sensor recognised a flat surface and fired.